Design and Synthesis of Novel PET Radiotracers for Imaging Sphingosine-1-Phosphate Receptor 5 (S1PR5) in the Brain

Sphingosine-1-phosphate receptor-5 (S1PR5) is highly expressed in oligodendrocytes and it plays an important role in neurodegenerative disorders like multiple sclerosis. We designed, synthesized, and determined the binding potencies of 27 novel S1PR5 ligands. Four radiotracers [¹¹C]7, [¹⁸F]7a, [¹¹C]12a, and [¹⁸F]12b were synthesized for the characterization of their in vitro and in vivo binding properties. [¹⁸F]7a had good rat brain uptake with 0.62%ID/g at 5 min, while the other three radiotracers had lower brain uptake. [¹⁸F]7a had K_d values of 2.2, 4.6, and 27.6 nM for recombinant human S1PR5 cell membranes, C57BL/6 mouse brain, and human cerebral cortex, respectively. Pretreatment with S1PR5 potent modulators effectively impacted rodent brain uptake of [¹⁸F]7a. Cuprizone-fed mice had reduced [¹⁸F]7a brain uptake, reflecting the loss of oligodendrocytes and decreased S1PR5 expression. [¹⁸F]7a also showed good brain uptake and retention in macaque, and no radiometabolites entered the rat brain, further supporting its potential as a promising radiotracer for imaging S1PR5 in the brain.